Tertiary-aminoalkyl 4-substituted-2-(tertiary-aminoalkoxy) benzoates and their synthesis



Patented June 16, 1953 I TERTIARY-'AMINOALKYL 4 SUBSTITUTED- 2 (TERTIARY AMINOALKOXY)BENZO- ATES AND THEIR. SYNTHESIS Raymond 0. Clinton, North Greenbush, and Stanley 0. Laskowski, Menands, N. Y., assignors to Sterling Drug Inc,, New York, N. Y., a corporation of Delaware No Drawing; Application September 5, 1951, Serial No. 245,246

This invention relates to tertiary-aminoalkyl 4 substituted 2 (tertiary-aminoalko-Xy)benzoates and to their synthe' is.

The compounds of our invention have the general formula where Z is nitro or amino, X and Y are each lower alkylene radicals, and NRRi and. NRzRs are each tertiary-amino radicals. These compounds are useful as pharmaceuticals and as intermediates in the preparation of pharmaceuticals, for instance, in the preparation of the corresponding quaternary salts which are disclosed and claimed in'our copending application Serial No. 245,249, filed September 5, 1951.

In the above general formula, the lower a1- kylene radicals designated as X and Y each has two to four carbon atoms and each has its two 23 Claims. (o1. 260-2472) radicals where R, R1, R2 and R3 are lower alkyl groups, alike or different, and each alkyl group having one to six carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, ethyl-n-propylamino, di-n-butylamino, di-n-hexylamino, and the like. Further, the tertiaryamino radicals designated as NRR1 and NRzRa each encompassed saturated N-heteromonocyclic radicals having five to six ring atoms, illustrated by examples such as l-piperidyl; (lower alkyl-' ated)-l-piperidyl such as Z-methyl-l-piperidyl, 3ethyl-l-piperidyl, 4-methy1-1-piperidyl, 2,6-dimethyl-l-piperidyl; l-pyrrolidyl; (lower alkylated) -1pyrrolidyl such as Z-methyl-l-pyrrolidyl, 2,5-dimethyl-l-pyrrolidyl; 4-morpholiny1; and the like.- For a given compound, NRR1 and NRzRa can be alike or different.

The compounds of our invention can be prepared by the procedure illustrated by the following series of reactions where X, Y, NRR1 and NRzRs are defined as above, R is alower alkyl radical and halogen is chlorine, bromine, iodine free valence bonds on different carbon atoms. 25 or fluorine: I

No; NO: N02

' II +halogenXNRR OH (B) O-X-NRRl OXNRR1 00B; 0003 I coon (A) (C) (D) Y halogenYNRiRa V (E) v i111 NHz NO:

IV O-X'NRR1 Thus, X and Y include such examples as CHzCH2-, CHzCHzGHzo0-Y-NRiRi JOO Y NRiR 1 (o) (r) .In step I, a lower alkyl' 4-nitro-2-hydroxybenzoate (A) is converted into a lower alkyl 4-nitro-' Z-(tertiary-aminoalkoiry)benzoate (C) by reaction with a tertiary-aminoalkyl halide (B). In

step II, the lower alkyl 4-nitro-2- (tertiary-amino i alkoxy) benzoate (C) is saponified to yield'the corresponding 4-nitro-2- (tertiary-aminoalkoxy) henzoic acid (D), which, instep III, is converted into a tertiary-aminoalkyl '4-nitro-2-(tertiaryaminoalkoxy)ben' zoate (F) by reaction with a tertiary-aminoalkyl halide (E). In step IV, the -nitro ester (F) is reduced to yield the corresponding tertiary-aminoalkyl l-amino-2-(ter- ,tiary-aminoallsoxy)benzoate (G). This series of reactions is illustrated as follows: Ethyl 4-nitro- 2-hydroxybenz0ate, preferably in the form of an alkali metal salt, is reacted with a Z-diethylaminoethyl halide, preferably the chloride, to yield ethyl 4-nitro-2-(2-diethylaminoethoxy) benzoate; this ethyl ester is saponiiied to yield the corresponding acid; the acid is treated with Z-(i-piperidyl) ethyl halide to form 2-(l-p idyl) ethyl 4-nitro2- (Z-diethylaminoethoxy) benzoate; and this a-nitro ester is reduced to form the corresponding 2-(1-piperidyDethyl a-amino- 2-(2-diethylaminoethoxy) benzoate.

Step I is carried out preferably using a lower alkyl l-nitro-2hydroxybenzoate in the form of a metal derivative, with a tertiary-aminoalkyl halide. Alternatively, step I can be carried out using a lower alkyl e-nitrc-2-hydroxybenzoate it-' self, however, with a resulting decrease in yield of the lower alkyl 4-nitro-2-(tertiary-aminoalkoxy)benzoate. The lower alkyl e-nitro-Z-(tertiary-aminoalkoxy)benzoates are disclosed and claimed in our copending application Serial No. 245,24 filed September 5, 1951.

Step I can also be carried out stepwise, that is, by first haloalkylating the lower alkyl l-nitro- Z-hydroxybenzoate (A) to form the lower alkyl l-nitro-Z-(haloalkoxy)benzoate which is then treated with a secondary amine having the formula HNRR1. The first step can be accomplished by treating a lower alkyl 4-nitro-2-hydroxybenzoate or a metal derivative thereof with a haloalkylating agent such as a halcalkyl para-toluenesulfonate, haloalkyl benzenesulfonate, dihaloalkane, etc. As illustrations of this stepwise procedure, ethyl e-nitro-2-hydroxybenzoate is haloalkylated by treating its sodium salt with. Z-chloroethyl para-toluenesulfonate to form ethyl 4-nitro-2-(2-chloroethoxy)benzoate which then is treated with diethylamine or piperidine to form ethyl 4-nitro-2- (Z-diethylaminoethoxy) benzoate or ethyl l-nitro-2-[2-(1-piperidy1) ethoxylbenzoate, respectively.

The esterification step III is carried out pref erably by heating a 4-nitro-2-(tertiary-aminoalkoxy)benzoic acid with a tertiary-aminoalkyl halide. [n'practice we found this reaction could be satisfactorily and conveniently carried out in refluxing propanol or ethanol using the e-nitro- 2- (tertiary-aminoalkoxy) benzoic acid in the form of its hydrochloride addition salt (alternatively, the free base form can be used) and using a tertiary-aminoalkyl chloride.

The reduction step IV is carried out either by chemical methods or by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. In practicing our invention, we used preferably iron and hydrochloric acid. Catalysts suitable when catalytic hydrogenation is employed include Raney nickel, platinum, palladium or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups.

The tertiary-aminoalkyl i-substituted-Z-(tertiary-aminoalkoxy) benzoates can be employed in the form. of their free bases or in the form of their salts with relatively non-toxic organic or inorganic acids. In practicing our invention, we

found it convenient to isolate our compounds in the form of their hydrochlorides. However, other acid addition salts are within the scope of our invention. Such salts include the hydrobromides, phosphates, sulfates, citi'ates, sulfamates, tartrates, succinates, acetates, benzoates, oleates, and the like.

The following examples illustrate specific embodiments of our invention.

(1) Lower ailcyl 4-m'iro-2-(tertiaryaminoalkoxy) beneoates alkyl 4-nitro-2- (tertiary-aminoalhoxy) benzoate.

Ethyl 4: nitro-2-(Z-diethylaminoethoxy) benzoate was prepared as follows: To a stirred re-.

fiuxing solution of 42.2 g. of ethyl 4-nitro-2-hydroxybenzoate in 1000 ml. of absolute alcohol was added slowly a solution of 4.6 g. of sodium in 500 ml. of absolute ethanol. To the resulting deep red solution was added, with stirring over a period of about twenty minutes, 27.1 g. of Z-diethylaminoethyl chloride and the resulting mixture was refluxed for about three hours. An addi tional 5 g. of Z-diethylarninoethyl chloride was then added and refluxing continued for an additional thirty minutes. The reaction mixture was cooled in ice, filtered, and the filtrate taken to dryness in vacuo. The residue was taken up in 500 ml. of ethyl acetate, the resulting solution filtered and the filtrate taken to dryness, yielding ethyl 4-nitro-2- (Z-diethylaminoethoxy) benzoate. This compound was converted into its hydrochloride addition salt by dissolving it in a small amount of ethyl acetate and treating the solution with an excess of 29% ethereal hydrogen chloride solution. The resulting precipitate of ethyl 4 nitro-2-(2-diethylarninoethoxy)benzoate hydrochloride was collected and recrystallized twice from isopropanol, yielding 45.5 g. of purified product, M. P. 1444445.? C. (con).

AnaL-Calcd. for CisllzzNzfis-Hclz C, 51.94; H, 6.40; CI, 10.22. Found: C, 52.08; H, 6.48; (31,1012.

Ethyl 4 nitro-2-(Z-diethylaminoethoxy)benzoate was also prepared stepwise as follows: A mixture of 84.4. g. of ethyl l-nitro-Z-hydroxybenzoate, 60.8 g. of powdered anhydrous potassium carbonate and 2000 ml. of meta-xylene was refluxed with stirring under a water trap until no more water was collected (three hours). The water trap was removed and 112.7 g. of Z-chloroethyl para-toluenesulfonate was added in one portion. Refluxing and stirring'were continued for an additional nineteen hours. The mixture was filtered while hot and the filter-cake was washed with hot toluene. The combined filtrate and washings were evaporated into dryness in vacuo, yielding a cream-colored solid as residue. Several recrystallizations of this solid from methanol and from n-pentane gave a 60% yield of ethyl e-nitro-2-(2-chloroethoxy)benzoate as pale amount of red solid. This mixture was treated with 2500 ml. of absolute ether, and the red solid was filtered off. The filtrate was taken down to dryness under reduced pressure, yielding, as an piperidyl)ethoxylbenzoate, respectively. g 5 oil, the product, n-butyl 4-nitro-2-(2-diethyl- Ethyl 4-nitro-2-[B-(I-piperidyl)propoxylbenaminoethoxy)benzoate. Thi ester was convertedzoate wa prepared as follows: To a stirred reinto its hydrochloride addition salt by dissolving fluxing solution of 84.4 g. of ethyl 4-nitro-2- it in a little absolute ether and treating the soluhydroxybenzoate in 1500 ml. of absolute ethanol tion with an excess of ethereal hydrogen chloride. was added in a fine streama solution of 9.2 g. 10 A pale cream-colored solid separated. The mixof sodium in 500 ml. of absolute ethanol. To the ture was cooled and the solidfwas collected and resulting solution was added dropwise over a washed with absolute ether. Three; recrystal period of fifteen minuts 65 g. of 3-(1-piperidyl) liz'ations of this solid from ethyl acetate yielded, propyl chloride and the resulting solution was as pale yellow needles, n-butyl 4-nitro-2-(2-direfluxed for twenty-four hours. The sodium ethylaminoethoxy)benzoate hydrochloride, M. P.' chloride was filtered off and washed with ethyl 1176-1186 C. (cor.). acetate. The combined filtrate and washings AnaZ.--Calcd. for C1'7H26N2O5'HC1: ND, 7.47; Cl, were taken down to dryness under-reduced pres- 9.46. Found: ND, 7.66; CI, 9.44. sure yielding a mixture of an oily residue and a Ethyl 4-nitro-2-(Z-dimethylaminoethoxy)bensmall amount of a red solid. To this mixture zoate was prepared as follows: To a solution of was added 2 liters of ether and the insoluble red 126.6 g. of ethyl 4-nitro-2-hydroxybenzoate in solid was filtered off. The filtrate was evapo- 1000 ml. of absolute ethanol was added a solurated to dryness under reduced pressure, yieldtion of 13.8 g. of sodium in 500 m1. of absolute ing, as an oily material, ethyl 4-nitro-2-[3- ethanol. The ethanol was then removed by dis- -p p p p ylb oa Th s ester was tillation while simultaneously adding toluene converted into its hydrochloride salt by dissolving (1000 ml.). To the resulting bright red suspenit in a little ethyl acetate and adding to the solusion of the sodium salt of ethyl 4-nitro-2-hytion an excess of ethanolic hydrogen chloride. droxybenzoate in toluene was added 66.3 g. of The solid hydrochloride separated slowly. The z-dimethylaminoethyl chloride and the mixture mixture was diluted with absolute ether, cooled, was refluxed with stirring for forty-eight hours. and the precipitate was collected and washed with The mixtur was filtered whilehot and the filterab ol ether- The p pitate was recrystalcake was washed with hot toluene. The comlized three times from isopropanol, yielding, as bined filtrate and washings were evaporated in pale yellow needles, ethyl 4-nitro-2-[3-(l-pipervacuo, leaving a quantitative yield of ethyl idyl)propoxylbenzoate hydrochloride, M. P. 4-nitro-2-(2-dimethylaminoethoxy)benzoate, as 160.4-161.6 (3'. (con). an oil. Treatment of an ethyl acetate solution AnaZ.-Calcd. for C17H24N2O5-HCI: ND, 752; this f with an amass 0f 20% P F C1 95L Found: ND, 737; C1, 1 hydrogen chloride gave a gummy prec1p1tate, ND stands for total nitrogen as determined by the whlch crystelhzed from lsopropanol 1n pal y l- Dumas method low needles, M. P. 202.2-202.6 C. (cor.). This n-Butyl 4-nitro 2 (Z-diethylaminoethoxy) g g g g gig g dlmethylammo benzoate was prepared as follows: To a stirred Anazraalcd for C13H18N2O5,HC1. ND 3379. refluxing solution of 9.2 g. of sodium in 2000 ml. C1 Found. ND 856; C1, .nbutaml was added n'butyl Additional lower alkyl 4-nitro-2-(tertiary- 4'n 1tm'2'hydroxybenzoate' t Insoluble aminoalkoxy) benzoates prepared according to i phemlate Separated Immediately" After the above described procedures are given in addition had beencomplete, refluxing was con- Table tinued for an additional ten minutes, and then I 54.2 g. of 2-diethylaminoethyl chloride was added TABLE I dropwise over a period of about twenty minutes. N When the addition had been completed, the color had already changed froma deep red to a paleorange-yellow. The reaction mixture was then refluxed for five hours, cooled and filtered. The (CH2),.NRR1.Ho1- filtrate was taken down to dryness under reduced (5 pressure yielding an oily residue and a small 00R! Analyses n Nam. R, I 5 5 Formula ND 01 Calcd Found Galcd Found onion; 1530-1540 C1EHMN205.HC1 7.24 7.15 9.15. 9.14 euros, 207.0208.0 CwHznNzOaHOl 7. 77 7.81 9.83 V 9.02- CHqCHs 142.0144.6 CmHziNzOaHCl 7.48 7,79 9.46 9.25 01120118 1910-1915 G1aH22N2Os.HCl 7.81 7.82 9.88 0.90 CH3 205.0-20s4 oaammotncl 1.04 4.05 10.22 10.21 011,011. 180. 8-1825 C1'lH24N205-HCI 7.52 7.22 9.51 9.38 omen. 158.2l59.6 01111121121105.1101 7. 24 7. 03 9.16 8.92 N(C2Ha)1 CHzCHa 164.8l65.6 CmHz4N2O5.HC] 7.77 7.87 9.83 9. 72 N am omomom. mar-155.4 owuzmzosnoi 7.77 7.95 9.83 9.83 N(C2H5)2 CH3 156.9159.2 C14H20N2O5-HCI 8. 42- 8.38 10. 65 10. 50.

Y Additional lower alkyl 4-nitrm2-(tertiaryaminoalkoxylbenzoates which can be prepared according to the foregoing procedures include the following: ethyl -nitro-ZI-(Z-dimethyleminol-propoxy)benzoate; isobutyl l-nitro-2-[3-(lpyrrolidyl) propoxylbenzoate; ethyl 4-nitro-2- [2 (2,5 dimethyl 1 pyrrolidyDethoxylbenzoate; methyl 4-nitr0-2-(-dimethylamino butoxy) benzoate; n-propyl 4-nitro-2- [2- (dinbutylamino) ethoxylbenzoate; n-butylel-nitro-2- (3-(4-methyl- 1 -piperidyl)propoxylbenzoate; nhexyl 4-nitro-2-l2 (3-ethyl-1-piperidyl)ethoxylbenzoate; n-amyl 1-nitro-2-[3-(2-methyl-1-pyrrolidyl)propoxylbenzoate; and the like.

(2) 4-m'tro-2-'(tertiary-aminoclko.ty)benzoic acids These acids are prepared by saponification of the corresponding lower alkyl esters as illustrated by the following examples.

4-nitro-2- (2-diethylaminoethoxy) benzoic acid was prepared as follows: A mixture containing g. of ethyl 4-nitro-2-(2-diethylaminoethoxy) benzoate monohydrochloride, 18.3 g. of sodium carbonate, 100 ml. of water and 100 ml. of 95% ethanol was refluxed for four hours. The ethanol was removed by distillingin vacuo and the remaining aqueous solution was diluted with water, acidified with concentrated hydrochloric acid and cooled, whereupon some solid separated. The mixture was saturated with ammonium sulfate, whereupon more solid separated. This solid was collected and recrystallized three times from methanol, yielding as pale yellow needles. i-nitro- Z-(Z-diethylaminoethoxy)benzoic acid in the form of its mohohydrochloride, M. P. 2125-2139 C. (-001).

AnaL-Calcd. for Cpl-haNzOs-HCl: C. 48.98; H, 6.01; Cl, 11.12; NNO2, 4.39. Found: C, 49.28; H, 6.13; Cl, 10.92; Nuo 4.21.

NNOZ stands for nitro nitrogen as determined-by titration with standard titanous chloride in glacial-acetic acid solution.

4-nitro-2- (Z-diethylaminoethoxy) benzoic acid is also obtained following the above procedure but using, in place. of ethyl e-nitro-2-(2-diethylaminoethoxy)benzoate hydrochloride, the corresponding methyl, n-propyl, n-butyl or n-hexyl 4-nitro-2- 2-diethylaminoethoxy) benzoate drochloride.

When the above procedure-"is followed but using, in place of ethyl 4-nitrb-2-(2-diethyl aminoethoxy)benzoate hydrochloride, ethyl 4- nitro-2-[3-(2-methyl- 1 -piperidyl) propoxylbenzoate, methyl 4-nitro- 2 2 -01 morpholinyl) ethoxy] benzoate, ethyl 4-nitro-2-[3-(4-morpholinyDpropoxylbenzoate or ethyl 4-nitro-2-[2- (2,6-dimethyl-l-piperidyl) ethoxyl benzoate, each either in the form of its free base or hydrochloride addition salt, there is obtained, respectively, 4- nitro-2-[3-(2-methyl- 1 -piperidyl) propoxylbenzoic acid, 4-nitro-2 [2(4-morpholinyl) ethoXylbenzoic acid, 4-nitro-2- [3- (4-morpholinyl) propoxylbenzoic acid or 4-nitro-2-[2-(2,6-dimethyll-piperidyl)ethoxylbenzoic acid.

When th above procedure was followed but using 113 g. of ethyl 4-nitro-2-[3-(1-piperidyl)- propoxylbenzoate monohydrochloride, 128.5 g. of sodium carbonate, 800 ml. of water and 800 ml. of 95% ethanol, and a reflux period of twenty-one hours, there piperidyl) propoxylbenzoic acid monohydrochloride, M. P. 216.8-2175" C. (con) when recrystallized twice from absolute ethanol.

was obtained 4-nitro-2-[3(1- Ana-Z.'Calcd. for C15H20N205 HCl: No, 8.16. Found: Cl, 10.09; ND, 8.1'7.

e-nitro 2 2 dimethylaminoethoxy)benzoic acid in the form of its monohydrochloride salt was prepared following the above procedure but using 15 g. of ethyl 4-nitro-2-(Z-dimethylaminoethoxy)benzoate, 16.9 g. of sodium carbonate, 100 ml. of water and 100 ml. of ethanol, and a reflux period of sixteen hours. The product, 4-nitro-2- 2-dimethylaminoethoxy) benzoic acid monohydrochloride, melted at 208.0-2096" C. (cor) when recrystallized three times from absolute ethanol.

Anal.--Calcd. for Ci1H14N205'I-IC1Z Cl, 12.20; Nuo 4.82. Found: Cl, 12.06; Nuo 4.70.

Additional 4-nitro-2- (tertiary-aminoalkoxy) benzoic acids which can be prepared according to the foregoing procedure include the following: 4-nitro- 2 2 -dimethylamino-lpropoxy) benzoic acid; 4-nitro-2-[3-(1-pyrrolidyl) propoxylbenzoic acid; 4-nitro-2- [2- (2,5-dimethyl-1pyrrolidyl') ethoxylbenzoic acid; 4-nitro-2-(4-dimethylaminobutoxy) benzoic acid; -nitro-Z-[2-(di-n-butylaminolethoxylbenzoic acid; i-nitro-Z-[B-(- methyl 1 piperidyl)propoxylbenzoic acid; 4- nitro-2-[2-(3-ethyl 1 piperidyl)ethoxylbenzoic acid; 4-nitro-2-[3-(2-methyl- 1 -pyrro1idyl)propoxylbenzoic acid; and the like.

(3) Tertiary-aminoalkyl 4-m'tro-2-(tertiaryaminoallcoxy benzoates These esters are prepared preferably by reactmg the corresponding 4-nitro-2-(tertiary-aminoalkoxy)benzoic acids with a tertiary-aminoalkyl halide, preferably the chloride, as illustrated by the following examples.

Z-diethylaminoethyl 4-nitro-2-(2-diethylaminoethoxy)benzoate was prepared as follows: A mixture containing 15.9 g. of 4-nitro-2-(2-diethylaminoethoxy benzoic acid monohydrochloride, 8.1 g. of Z-diethylaminoethyl chloride and 200 ml. of isopropanol was refluxed for seven hours and then allowed to. stand at room temperature overnight. Rosettes of white needles which had separated were collected. The filtrate was concentrated in vacuo, cooled and diluted with ethyl acetate, whereupon av small amount of additional white solid separated. This solid was collected and combined with the first crop of white needles; the combined crops were dissolved in a little water; and the aqueous solution was treated with an excess of 35%.aqueous sodium hydroxide solution. The mixture was saturated with sodium chloride and was extracted exhaustively with ethyl acetate. The ethyl acetate extract was dried over anhydrous calcium sulfate and the ethyl acetate was removed by distilling under reduced pressure, thereby yielding as a straw colored mobile oil, 2-diethylaminoethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate. This ester was converted into its dihydrochloride salt by dissolving it in a minimum amount of ethyl acetate and adding to the solution an excess of ethereal hydrogen chloride. There separated an oil which solidified when cooled and triturated. The solid was'collected and recrystallized three times from absolute ethanol, yielding 2-diethylaminoethyl 4-nitro-2-(2 diethylaminoethoxy) benzoate dihydrochloride, M. P. 1930-1939, C. (c0r.).

AnaZ.Calcd. for C19I-1'31-N3O52HC1: C, 50.22; 11,732; C1, 15.61. Found: C, 50.44; H, 7.38' 01, 15.45.

Following the above procedure but using, in place of 4-nitro-2-(2-diethylaminoethyoxy) bentro-2-[2-(2,6 "zoate.

2010 acid monohydrochloride, 4-nitro-2-[3-(2- methyl 1 piperidyl)propoxylbenzoic acid, 4-

nitro-2-[2-(4-morpholinyl) ethoxylbenzoic acid,

I 3-(1-piperidyl) propyl 4-nitro-.2-(2 -diethylaminoethoxy)benzoate was prepared as follows: A

Tmixture containing 31.9 g. of 4-nitro-2-(2-diethylaminoethoxy)benzoic acid 'monohydrochloride, -19.4 g. of 3-(1-piperidyl) propylichloride' and 600 ml. of isopropanol was refluxed fortwenty-three hours. The 'reactionmixture was cooled, diluted with water and the isopropanol was removed by distilling in vacuo. The remaining aqueous solution was cooled, made alkaline with aqueous sodium hydroxide. solution and the liberated oil was taken up with ethyl acetate. The aqueous layer was saturated with sodium'chloride and extracted two additional times with ethyl acetate. The combined ethyl'acetate layers were dried over anhydrous calcium sulfate. A small amount of solid that separated'from the'dried' ethyl acetate solution was filtered offand the filtrate was concentrated by distilling in vacuo, yielding 3-(1-piperidyl) propyl 4-nitro-2 (2 'diethylaminoethoxy) benzoate. This ester was converted into its dihydrochloride addition salt by dissolving it, with warming, in a little ethyl acetate, filtering the solution to remove a small amount of insoluble solid, cooling the filtrate and adding thereto an excess of ethereal hydrogenchloride,whereupon a solid separated, The mixture was cooled and diluted with ethyl acetate. The solid was collected and wasrecrystallized four times from absolute ethanol, yieldi'ng 3-(l-rpiperidyl) propyl 4- nit'ro- 2 (2-diethylaminoethoxy)benzoate dihydrochloride, M. P. 214.42l 5.2 C. (con),

Anal-Calm. for Carl-133N305.21-ICl: C1, 1436'; Nno 2.92. Found: Cl, 14.60; ,NNo 3.12.

Following the foregoing procedure but using,

' ethylaminoethoxy)'benzo'ic' acid monohydrochloride, 18 g. of 2-(4-morpholinyl) ethyl chloride and 600 ml. of absolute ethanol. was. refluxed for twenty hours, filteredwhile' hot and then concentrated-in -ivacuo to remove the solvent. The oily residue crystallized when triturated withdry acetone. This crystalline solid was collected,

washed with ethyl acetat and dissolved in water. -The aqueous solution was made alkalinewith ammonium hydroxide and the'oil that separated was taken up with ethyl acetate. The aqueous -'layer was saturated with sodium chloride and extracted two additional times with ethyl acetate. The combined ethyl acetate extracts were'dried over anhydrous calcium sulfate, Somesolid material that separated from the dried ethyl acetate solution was filtered and the filtrate wascon-.

centrated in vacuo to yield a small amount of oily product, 2-(4-morpho1inyl) ethyl 4-nitro-2- (2-diethylaminoethoxy)benzoate. The oily prodnot was converted into its dihydrochloride by dissolving it, with warming, in a minimum quantity of ethyl acetate, filtering to remove some'insoluble material, cooling the filtrate and adding thereto an excess of ethereal hydrogen chloride, whereupon an oil separated. The mixture ,was diluted .with absolute ether to insure complete precipitation. The solvents were removed by decantation and the oily material crystallized when triturated with dry acetone. The crystalline product was recrystallized three times from absolute ethanol, yielding 2-(4-morpholinyDethyl 4- nitro-2 -(2 diethylaminoethoxy) benzoate dihydrochloride, M. P. 2l7.0-218.0 C. (con). j'

Anal.-'Cal-cd. for CmI-IzgNaOa-ZHCl: C1, 15.14; Nuo 2.99. Found: Cl, 14.90; Nuo' 2.95.

3 (l-piperidyDpropyl 4-nitro-2-[3-(1-piperidyllpropoxylbenzoate was prepared as follows:

A mixture containing 34.5 g. of 4-nitro-2-[3'-(1- piperidyl) propoxyl benzoic acid monohydrochloride, 19.4 g. of 3-(l -piperidyl) propyl chloride and 600 ml. of isopropanol was refluxed for twentyfour hours, evaporated under reduced pressure to remove this solvent, thereby yielding a solid residue. The solid was suspended in ethyl acetate, filtered and washed with ethyl acetate. This solid was dissolved in Water, the solution was treated with concentrated ammonium hydroxide and the oil that separated was extracted with ether. The ether extract was dried over anhydrous calcium sulfate. Removal of the ether under reduced pressure yielded the oily product, 3 (1 piperidyDpropyl 4-nitro-2-[3-(1-piperidyl) -propoxyl7nenzoate. This ester was convert- :ed into its dihydrochloride salt as follows: To a solutionof 23 g. of 3-(1-piperidyl)propyl 4-nitro- 2 [3 (l-piperidyl) propoxylbenzoate dissolved in a minimum amount of ethyl acetate was added an excess of ethereal hydrogen chloride, where- ;upon a whitesolid separated. The mixture was diluted with ethyl. acetate and allowed to stand for one hour. The solid was filtered, washed :with ethyl 'acetate and then recrystallized once from absolute ethanol-isopropanol and 'once from absolute ethanol, yielding, as rosettes" of cottony white needles, 3 (1-piperidyl)pr0pyl 4- tro 2 [2 (di-n-butylamino)ethoxylbenzoate; Z-di-n-butylaminoethyl 4-nitro-2- [3- i-methyll-piperidyl)propoxylbenzoate; 2 (3 ethyl-lpiperidyl) ethyl 4-nitro-2-[2-(3-ethyl-1-piperidyl) ethoxy] benzoate; 3- (4-morpholiny1) -propyl 4 nitro-2-[3-(2-methyl-1-pyrrolidy1)propoxylbenzoate; and the like.

(4) Tertiary-aminoalkyl 4-amz'no-2-(tertiaryaminoalkozry) benzoates These esters can be prepared by reduction of the corresponding tertiary-aminoalkyl l-nitro- 2-(tertiary-aminoalkoxy)benzoates. This procedure is illustrated as follows.

2 diethylaminoethyl e-amino-2-(2-diethylaminoethoxy)benzoate can be prepared as follows: To a solution of 4.5 g. of z-diethylaminoethyl 4-nitro-2-(Z-diethylaminoethoxy) benzoate dihydrochloride in 150 ml. of ethanol is added 0.3 g. of platinum oxide monohydrate, and the mixture is treated with hydrogen at 50 lbs. per square inch of pressure at room temperature. The reduction is rapid and exothermic. The catalyst is filtered oil and the filtrate is evaporated to dryness under reduced pressure, yielding a solid residue of 2-diethylaminoethyl 4-amino-2-(2-diethylaminoethoxy)benzoate in the form of its dihydroohloride, which can be recrystallized from absolute ethanol to yield a substantially pure product. The dimethiodide salt of this ester melts at 210.5'-2l1.9 C. (con).

Following the above procedure but using, in

place of 2-diethylaminoethyl 4-nitro-2-(2-diethylaminoethoxy) benzoate dihydrochloride, 3-

(1 piperidyl)propyl 4-nitro-2-(2-diethy1aminoethoxy) benzoate, 2 l-morpholinyl) ethyl 4-mtro 2 (2-diethy1aminoethoxy)benzoate, 3-(1- piperidyDpropyl 4-nitro-2 [3-(1-piperidyDpropoxylbenzoate, Z-diethylaminoethyl 4-nitro-2- [3 (Z-methyl-l-piperidyl)propoxylbenzoate, 2- diethylaminoethyl -nitro-Z- [2- (-morpholinyl) ethoxylbenzoate, Z-diethylaminoethyl a-nitro-z- [3- (4-morpholinyl)propoxylbenzoate or 2-diethyl aminoethyl 4-nitro-2-[2-(2,6-dimethyl-l-piperidyDethoxylbenzoate, each either in its free base form or in the form of its dihydrochloride addition salt, there is obtained, respectively, 3-(1- piperidyl) propyl 4 amino-2-(2-diethylaminoethoxy)benzoate, 2 (4 morpholinyDethyl 4- amino-2- (2-diethylaminoethoxy) benzoate, 3- (lpiperidyl) propyl amino-2-[3-(1-piperidyl) propoxylbenzoate, Z-diethylaminoethyl 4-amino- 2 [3 (2-methyl-l-piperidy1)propoxylbenzoate, Z-diethylamino 4 amino-2-[2-(l -morpholinyl) ethoxylbenzoate, 2-diethylaminoethyl 4-amino- 2-[3-(4-morpholinyl)propoxylbenzoate or 2-diethylaminoethyl l-amino 2 [2-(2,6-dimethyll-piperidyl) -ethoxy]benzoate.

Additional tertiary-aminoalkyl 4 amino-2- .(tertiary-aminoalkoxy)-benzoate which can be prepared according to the foregoing procedure include the. following: 4-diethylaminobutyl 4- amino 2 KZ-dimethylamino-l-propoxy)benzoate 3- l-pyrrolidyl) propyl 4-amino-2- [3- (lpyrollidyl)propoxylbenzoate; Z-dimethylaminoethyl 4-amino-2- [2- (2,5-dimethyl-l-pyrrolidyl) ethoxylbenzoate; 3 (2 methyl-l-pyrrolidyD- propyl 4-amino-2- (i-dimethylaminobutoxy) benzoate; 2 (2,-6 dimethyl-l-piperidyl) ethyl 4- amino 2- [2-(di-n-butylamino) ethoxyl benzoate; 2 di n butylaminoethyl 4 amino-2-[3-(4- methyl-l-piperidyl) propoxy] benzoate; 2 (3 -ethyl 1 piperidyl) ethyl l-amino-2-[2-(3-ethyl-1- piperidyl) ethoxy] benzoate; 3- (a-morpholinyl) 12 propyl 4 amino-2-[3-(2-methyl-l-pyrro1idyl)- propoxylbenzoate; and the like.

We claim: 1. A compound having the formula where Z is a member of the group consisting of nitro and amino, X and Y are each lower alkylene radicals whose two free valence bonds are on difierent carbon atoms, and NRR1 and NRzRs are each members of the group consisting of dialkylamino, l-piperidyl, (lower alkylated)-1- piperidyl, l-pyrrolidyl, (lower alkylated) -1-pyrrolidyl and -morpholinyl.

2. A compound having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms.

3. A compound having the formula NO: @O-QI-NK 0111:):

where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms.

4. A compound having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on difierent carbon atoms and NRzRa is a l-piperidyl radical.

5. A compound having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms and NR2R3 is a l-piperidyl radical.

' 6. A compoundhaving the formula Q 1 O-X-N(lower alkyl);

o'o-v-Nm'n', v v where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms and NRzRa is'a 4-morpholinyl radical.

7. A compound having the formula OO-Y-NRzR where X and Y are each lower alkylene radicals 7 whose two free valence bonds are on different where X and Y are each loweralkylene radicals whose two free valence bondsare on different carbonatoms, and NRRiand N'RzRs are each 1+ piperidyl radicals. J

9. A process for the preparationpf a come pound having the formula; 4

OXNRR1 oo-Y Nmnl where X and Y- are each lower alkylene radicals whose two free valence bonds are on different carbon atoms; and NRR1 and NRRa are each members of the group consisting of dialkylamino,

' l-piperidyl; (lower alky1ated)-1-piperidyl, l-pyrrolidyl, (lower alkylatedi-"l-pyrrolidyl and 4- morpholinyl, which comprises heating the. corresponding 4 nitro 2 (tertiary-aminoalkoxy) benzoic acid with a tertiary-aminoalkyl halide having the formula, halogen-Y NR2Rs. j

10. A process for the preparation of a compound having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, which comprises heating the corresponding 4-nitro-2- (dialkylaminoalkoxy) benzoic acid with a dialkylaminoalkyl halide having the formula, halogen Y-N (lower alkyD-z.

l-LJA process forthe preparation of .alcompound having the formula: IFOIV f n OX-N(C'5Hs)q COO- -N (C2Hs)2 where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, which comprises heating the corresponding 4w-nitro-2- (diethylaminoethoxy) benzoic acid with a diethylaminoalkyl halide having the formula, halogenY-N(C2H5)z.

12. A process for the preparation of a compound having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms and NRzRc is a l-piperidyl radical, which comprises heating the corresponding 4- nitro-2-(dialkylaminoalkoxy)benzoic acid with a tertiary-aminoalkyl halide having the formula, hailogen-YNB2Ra.

13 Aprocess for the preparation of a compound-shaving the formula o-x-mormp where X and Y are each lower alkylene radicals whose two free valence bonds are on difi'erent carbon atoms andlNRaRa is a l-piperidyl radical,

which comprises heating the correspondinggnitroi-2-(diethylaminoalkoxy)benzoic acid with a tertiary-aminoalkyl halide having the formula, halogen-Y-N'RaRs.

14. A process for the preparation of a com- I pound having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms and NRzRs is a'A-morpholinyl radical, which comprises heating the corresponding 4-nitro-2-(dialkylaminoalkoxy)benzoic acid with a] tertiary-aminoalkyl halide having the formula, hal0gen-Y-NR2Rc.

-15. A process for the preparation of a compound having the formula Where X and Y- are each lower alkylene radicals where X and Y are each lower alkylene radicals whose two free valence bonds are on difierent carbon atoms, and NRR; and NRzRc are each 1- piperidyl radicals, which comprises heating the corresponding 4 nitro 2 (tertiary-aminoalkoxy benzoic acid with a tertiary-aminoalkyl halide having the formula, halogen-YNRzRa.

l7. 2-diethy1aminoethy1 4-nitro-2-(2-diethylamin'oethoxymenzoate having the formula '0 cmommomm v 19. 2-(4-morp'holinyDethyl 4-nitro-2-(2-diethylaminoethoxylbenzoate having the *formula 2 V whose two free valence "1'6 20. 3-(1 piperid-yl) propyl 4 nitr'o-Z- [3 (1- piperidyl)propoxylbenzoate having the formula CH GH CH2 CHPCn GHQ-0H,

CH; OHz-Ca 21. A compound having the formula OXN(lower alkyl):

0 0Y'N 1ower tlkyl);

Where X andY are each lower alkylene radicals whose two free valence bonds are on different carbon atoms.

22. A compound having the formula 0XN(G2Hs)z o-o-Y-'N o,H5- 2 where X and Y are each lower alkyleneradicals bonds are on different carbon atoms. j i

23. 2-diethylaminoethyl A-amino-Z-(Z-diethylaminoethoxy)benzoate having the formula IETH:

0 0 H2 0 H2N 2 5) :I

O0 CHICH2N( 02 92 RAYMOND o cmrrron. STANLEY c. LASKVOWSKI.

No references cited. 

1. A COMPOUND HAVING THE FORMULA 